NOVEL CCK-B RECEPTOR AGONISTS - DIKETOPIPERAZINE ANALOGS DERIVED FROMCCK4 BIOACTIVE CONFORMATION

Recently, we proposed a CCK-B agonist bioactive conformation character ized by an 'S' shape of the peptidic backbone which was derived from s tructure-activity relationships and conformational analysis of CCK4 (T rp-Met-Asp-Phe-NH2) analogues. Using this template, we report here the synthesis of cyclic CCK4 analogues which contain, in place of the Trp -Met dipeptide, a diketopiperazine moiety resulting from a cyclization between Nle and N-substituted (D)Trp residues and coupled with a smal l linker to Asp-Phe-NH2. Some of these compounds displayed good affini ties and selectivities for the CCK-B receptor. The results are discuss ed in terms of size, hydrophobicity and spatial orientation of the sid e-chains on the diketopiperazine ring. The most potent ligand exhibite d potent and full CCK-B receptor agonist properties in promoting the h ydrolysis of inositol phosphates (EC(50) = 8 nM) in CHO cells, stably transfected with the rat brain CCK-B receptor. This compound was also shown to be a potent selective CCK-B/gastrin receptor agonist since, i t increased gastric acid secretion measured in anesthetized rats on i. v. administration. These compounds provide a rigid template for the de sign of non-peptide CCK-B agonists, by modification of the remaining p eptide moiety.